Alcoholism is a common disease, affecting 4-5% of the population (reviewed by Zernig et al., 1997). In 1990, the cost of alcoholism and alcohol abuse to U.S. society was estimated at $136 billion (reviewed by Diamond, 1992). Despite these facts, our understanding of how alcohol affects behavior and brain function is incomplete. This proposal describes the identification of a mutation (EP1455) in a Drosophila MAPKKK gene, which causes an altered behavioral response to ethanol, cocaine, and nicotine. MAPK signaling is altered upon exposure to chronic ethanol in both rats and human hepatocyte cell culture (Chen et al., 1998; Kishore et al., 2002; Nelson et al., 2003), indicating that MAPK pathways are likely important targets for ethanol's effects on the brain. The goal of this project is to use EP1455 and the abundant genetic tools available in Drosophila to investigate the role of MAPK signaling in the response to ethanol. The specific aims of this proposal are: [unreadable] 1. Determine the spatial and temporal requirements for the MAPKKK encoded by CG14217. [unreadable] 2. Characterize the functions of the kinase and PERM domains in the function of CG14217. [unreadable] 3. Investigate the function of MAP kinase signaling in drug response. [unreadable] [unreadable]